The EMPEROR-Reduced Phase III clinical trial by Boehringer Ingelheim and Eli Lilly and Company found that empagliflozin, a diabetes medication, is a safe and effective treatment for heart failure with reduced ejection fraction. Empagliflozin was found to significantly reduce the risk of cardiovascular death and hospitalisation for heart failure in adults with and without diabetes, who also suffered from heart failure with reduced ejection fraction. The results of this trial, and other trials under the EMPOWER programme from the alliance between the two companies, could change the way cardio-renal-metabolic conditions are treated.
by Oh Sher Li
Cardiovascular disease continues to be the leading cause of death worldwide, due to the many types of complications that arise and the severity of several cardiovascular conditions. Even if the condition does not result in death, it often has lasting effects on the patient’s way of life.
Heart failure occurs when the heart is unable to pump sufficient blood around the body. While it may not be immediately fatal, it leaves the heart greatly weakened and requires prolonged treatment. Observable symptoms of heart failure include fatigue, breathlessness, persistent coughing or wheezing, oedema, or an increased heart rate.
In Southeast Asia, patients tend to present with acute heart failure at a younger age, as compared to patients from Western countries such as America. However, Southeast Asian patients also display more severe clinical features and have less optimistic disease outcomes.
There are two types of heart failure – left-sided and right-sided heart failure. Left-sided heart failure is often a result of other cardiovascular conditions such as coronary artery disease, a heart attack, long-term hypertension, arrhythmia, cardiomyopathy, congenital heart defects, heart valve disease, or other risk factors such as diabetes mellitus, obesity and smoking. Right-sided heart failure generally develops as a result of advanced left-sided heart failure. Simply put, the presence of several pre-existing conditions, including diabetes and heart-related illnesses, can lead to heart failure.
Left-sided heart failure can be further categorised into heart failure with reduced ejection fraction (HFrEF), or heart failure with preserved ejection fraction (HFpEF), which are set apart based on the reason why the heart fails to pump enough blood to the rest of the body. HFrEF occurs when the left ventricle does not contract effectively, causing less blood to be pumped out during each contraction as compared to a normally functioning heart. This is often associated with myocardial infarction, or heart attacks, when the heart muscles are weakened. In contrast, HFpEF refers to the situation where the heart muscle contracts normally, but the left ventricle is unable to relax and properly fill with blood before contracting. This is associated with aging and hypertension.
The urgency with finding effective treatments for heart failure lies in the high mortality rate associated with heart failure-related hospitalisation and re-hospitalisation. Approximately one-third of patients die within one year of hospitalisation for heart failure, and the median survival reduces after each hospitalisation event, particularly for older individuals. In fact, approximately half of heart failure patients die five years after onset of the condition. There is also substantial burden on patients’ mental wellbeing and quality of life as they experience problems with physical mobility, making caring for themselves difficult, and have to take on the mental toll of repeated hospital admissions.
In a bid to overcome these problems and improve patient outcomes, Boehringer Ingelheim and Eli Lilly and Company embarked on the EMPEROR-Reduced trial, which tests empagliflozin as a treatment for HFrEF. Results of the successful Phase III clinical trial were announced in September 2020 at the annual meeting of the European Society of Cardiology – the ESC Congress 2020 – and published in The New England Journal of Medicine.
Empagliflozin, commonly known by its commercial name Jardiance®, is a common medication used for treatment of diabetes mellitus. It is a highly selective inhibitor of the sodium glucose co-transporter 2 (SGLT2), and when used for diabetes treatment, is meant to prevent sugar from being re-absorbed by the kidneys, so that excess sugar is excreted from the body. Empagliflozin also prevents salt re-uptake, allowing excess salt to be excreted as well, and as a result reduces the intravascular volume, or the volume of blood in a patient’s circulatory system. Researchers have hypothesised that the changes exerted by empagliflozin on sugar, salt and water metabolism in the body could contribute to its cardioprotective effects.
The EMPEROR-Reduced trial showed that administration of empagliflozin significantly reduced cardiovascular death or first hospitalisation for heart failure by 25 percent. It also significantly reduced total heart failure-related hospitalisations, including first and recurrent heart failure hospitalisations, by 30 percent. Exploratory analyses also showed that empagliflozin decreased the risk of detrimental effects on the kidneys, such as end stage kidney disease or a profound loss of kidney function, by 50 percent.
The performance of empagliflozin as a heart failure treatment was also tested in patients who had other pre-existing conditions such as diabetes or impaired kidney function. In these tests, the effect of empagliflozin remained consistent regardless of the presence of various comorbidities. Since heart failure is often associated with other ailments, these findings demonstrate that empagliflozin would be an effective treatment for heart failure in real-world scenarios where patients present with several health conditions in addition to heart failure.
As part of the Phase III clinical trial, the safety profile of empagliflozin was also thoroughly investigated. Reassuringly, empagliflozin was not found to increase rates of hypotension (low blood pressure), hypovolemia (volume depletion), or hypoglycaemia (low blood sugar), and no cases of ketoacidosis were found.
All of these results point to empagliflozin being a promising treatment for HFrEF, which could change medication guidelines and revolutionise the way diabetic patients with heart failure are treated.
The EMPEROR-Reduced trial is part of the EMPOWER programme spearheaded by Boehringer Ingelheim and Eli Lilly and Company. It aims to explore the impact of empagliflozin on major cardiovascular and renal outcomes in several prominent cardio-renal-metabolic conditions. EMPOWER consists of eight clinical trials and two real-world evidence studies, including a previous study, EMPA-REG OUTCOME®, which assessed the use of empagliflozin in adults with type 2 diabetes and established cardiovascular disease to prevent major adverse cardiovascular events, such as cardiovascular death.
“Empagliflozin was the first SGLT2 inhibitor to demonstrate a reduction in cardiovascular death and hospitalisation due to heart failure in people with type 2 diabetes and established cardiovascular disease, based on the EMPA-REG OUTCOME® trial. We continue to break new ground with the EMPEROR-Reduced results, which provide robust evidence that empagliflozin can transform the lives of millions of people through reducing cardiovascular outcomes and slowing the progression of kidney damage in people with heart failure. We look forward to exploring these data further and are planning regulatory submissions for later this year,” says Waheed Jamal, M.D., Corporate Vice President and Head of CardioMetabolic Medicine at Boehringer Ingelheim.
“Tens of millions of people live with heart failure and kidney disease, including many who also have diabetes. Results from EMPEROR-Reduced show that empagliflozin can help improve heart failure outcomes while also slowing kidney function decline. We are excited to share these data and, through our ongoing EMPOWER programme, hope to redefine how people living with these conditions are treated,” says Jeff Emmick, M.D., Ph.D., who is Vice President of Product Development at Eli Lilly and Company.
Following the outcomes of the trial, empagliflozin has been granted Fast Track designation by the U.S. Food and Drug Administration (FDA) for reducing the risk of cardiovascular death and hospitalisation for heart failure. This designation applies to both the EMPEROR-Reduced and EMPEROR-Preserved trials, with the latter investigating the use of empagliflozin for treatment of HFpEF, and whose results are expected in 2021.
As the prevalence of cardio-renal-metabolic conditions increases worldwide and ailments such as heart failure become more common especially in Southeast Asia, it becomes increasingly important to find effective treatment methods for serious conditions like heart failure that could impact a sizeable population. Collaborative studies between companies and trials like these could bring hope to patients and open new doors for research into therapeutics and disease treatment. [APBN]
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